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Chalcone Derivative L6H21 Reduces EtOH + LPS-Induced Liver Injury Through Inhibition of NLRP3 Inflammasome Activation

Authors
  • Kong, Xiaoxia
  • Wu, Guicheng
  • Chen, Sha
  • Zhang, Lihua
  • Li, Fengyuan
  • Shao, Tuo
  • Ren, Li
  • Chen, Shao-Yu
  • Zhang, Hongyu
  • McClain, Craig J.
  • Feng, Wenke
Type
Published Article
Journal
Alcoholism Clinical and Experimental Research
Publisher
Wiley (Blackwell Publishing)
Publication Date
Jun 30, 2019
Volume
43
Issue
8
Pages
1662–1671
Identifiers
DOI: 10.1111/acer.14120
PMID: 31162673
PMCID: PMC6790986
Source
PubMed Central
Keywords
License
Unknown

Abstract

Background: Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. (E)-2,3-dimethoxy-4′-methoxychalcone (L6H21), a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and nonalcoholic fatty liver disease. However, the use of L6H21 in alcoholic liver disease to inhibit exotoxin-associated inflammation has not been explored. In this study, we examined the effects of L6H21 on EtOH + LPS-induced hepatic inflammation, steatosis, and liver injury and investigated the underlying mechanisms. Methods: C57BL6 mice were treated with 5% EtOH for 10 days, and LPS was given to the mice 6 hours before sacrificing. One group of mice was supplemented with L6H21 with EtOH and LPS. RAW264.7 cells were used to analyze the effects of L6H21 on macrophage activation. Results: EtOH + LPS treatment significantly increased hepatic steatosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were reduced by L6H21 treatment. EtOH + LPS treatment increased hepatic inflammation, as shown by the increased hepatic protein levels of Toll-like receptor-4, p65, and p-IjB, and increased oxidative stress, as shown by protein carbonyl levels and reactive oxygen species formation, which were reduced by L6H21 treatment. In addition, L6H21 treatment markedly inhibited EtOH + LPS-elevated hepatic protein levels of NLRP3, cleaved caspase-1, cleaved IL-1β, and caspase-1-associated apoptosis. Conclusions: Our results demonstrate that L6H21 treatment inhibits EtOH + LPS-induced liver steatosis and injury through suppression of NLRP3 inflammasome activation. L6H21 may be used as an alternative strategy for ALD prevention/treatment.

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